Inhibition of enterotoxin-stimulated secretion in CACO-2 cells by 2-chloroadenosine

Bacteria that produce heat-stable enterotoxin (ST) are a leading cause of secretory diarrhea. ST activates an intestinal-specific guanylyl cyclase (GC-C), leading to the accumulation of intracellular cyclic GMP which results in the opening of the CFTR chloride channel, triggering secretion. Although the signaling cascade mediating ST-induced diarrhea is well characterized, anti-secretory therapy targeting this pathway has not been developed. We examined the ability of 2-chloroadenosine (2ClAdo), an inhibitor of guanylyl cyclase activity, to prevent ST-induced water secretion in Caco-2 intestinal cells. ST induced a chloride current and stimulated net basolateral-to-apical water secretion in these cells, effects that were mimicked by 8-bromocyclic GMP. Pretreatment of cells with 2ClAdo prevented ST-induced chloride current and water secretion, demonstrating that disruption of guanylyl cyclase signaling may be an effective strategy for anti-secretory therapy, and provides the basis for developing mechanism-based treatments for diarrhea caused by enterotoxigenic bacteria.